1-naphthylmethyl-2-lower alkyl-1, 2, 3, 4-tetrahydroisoquinolines



United States Patent Office 3,l53,h43 Patented Get. 13, T954 Thisinvention relates to new 1-naphthylmethyl-2-loweralkyl-1,2,3,4-tetrahydroisoquinolines having pharmacodynamic activity.More specifically the new compounds of X this invention have antipyreticand central nervous sys tem depressant activity. In addition, compoundsof this invention are useful as intermediates in the preparation of theN-lower alkyl-3,4-benzonoraporphines of my copending application SerialNo. 229,992

The new isoquinoline derivatives of this invention are represented bythe following structural-formula:

Formula I when:

R represents hydrogen or lower alkoxy, preferably meth- R representshydrogen, lower alkoxy, preferably methoxy or, when taken together withR, methylenedioxy;

R represents lower alkyl and R represents hydrogen or lower alkyl.

The terms lower alkyl? and lower alkoxyf where used herein. denotesgroups having 1-4 carbon atoms.

This invention also includespharmaceutically acceptable salts of the"above defined bases formed with non-toxic organic and inorganic acids."Such salts are easily prepared by methods known to the art. The base isreacted with either the calculated amount of organic or inorganic acidin aqueous miscible solvent, such as acetone or ethanol, with isolationof the salt by concentration and cooling or an excess of the acid inaqueous immiscible solvent, such as ethyl ether or chloroform, with thedesired salt separating directly. Exemplary of such organic salts arethose with maleic, fumaric, benzoic, ascorbic, parnoic, succinic,

bismethylenesalicylic, methanesulfonic, ethanedisulfonic,

acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic,mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic,glycolic, paminobenzoic, glutamic, benzene sulfonic and theophyllineacetic acids as well as with the 8-halotheophyllines, for example,8-brornotheophylline. Exemplary of such inorganic salts are those withhydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitricacids. Of course, these salts may also be prepared by the classicalmethod of double decomposition of appropriate salts which is well-knownto the art.

In addition, this invention includes pharmaceutically acceptable,nontoxic quaternary ammonium salts of the above defined bases formedwith, for example, a reactive lower alkyl halide, sulfate, p-tolueuesulfonate, benzene sulfonate or lower alkyl sulfonate. Y

The l-naphthylmethyl-Z-lower alkyl-l, 2, 3, 4-tetrahydroisoquinolines ofthis invention are prepared by condensing an isoquinolinium salt withl-nitro-Z-methylnaphthalene in alcoholic base such as sodium alkoxide ina lower alkauol. The reaction is carried out at about 18-45 C.,conveniently at room temperature, to give thel-(l-nitro-2'-naphthal)-2-lower alkyl-l,2,3,4-tetrah droisoquinolineintermediate. Hydrogenation of this intermediate in lower 'alkanolsolution in the presence of a catalyst such as platinum oxide orpalladium-in-charcoal gives the 1-(1'-arnin o-2'-naphthylmethyl)-2-loweralkyl 1,2,3,4-tetrahydroisoquinoline.

Alternatively, the 1-(1'-amino2'-naphthylmethyl)-2- loweralkyl-l,2,3,4-tetrahydroisoquinolines of this invention are prepared bycondensing a 3-substituted phenethylamine or aria-lower alkyl derivativethereof with l-nitro- Z-naphthalene acetyl chloride to give an amidewhich is cyclized by the Bischler-Napieralski reaction using adehydrating agent such as prosphorus oxychloride in an anhydroushydrocarbon solvent such as benzene or toluene at elevated temperature,conveniently at the reflux temperature of the reaction mixture, for areaction period of about 15-120 minutes.

The resulting 1-(1-nitro-2'-naphthylmethyl)-3,4-dihy droisoquinoline istreated with a lower alkyl "halide to give the corresponding N-loweralkyl isoquinoliniurn halide. Reduction of this intermediate with abimetallic hydride such as sodium borohydride and treatment of theproduct with zinc dust and sulfuric acid gives the 1(1'-amino-2'-naphthylmethyl)-2 lower alkyl-1,25,4-tetrahydroisoquinoline.

Cyclization by-the Pschorr procedure of a 1-(1'-amino-2'-naphthylmethyl)-2-lower alkyl 1,2,3,4 tetrahydroisoquinolinedihydrochloride, prepared by treating the base with excess etherealhydrogen chloride, gives the N-lower alkyl-3,4-benzonoraporphines havingpharmacodynamic activity.

The following examples are not limiting but are illustrative ofcompounds of this invention.

.Example. 1

Isoquinoline methiodide g.) and 70g. of 2-methyll-nitronaphthalene areadded to a warm ethanol solution of sodium (25 g.). The resultingsolution is kept at 25 C. for 24 hours and filtered to yield solidmaterial which is recrystallized from methanol to givel-(1'-nitro-2'-naph- M th a1) -2-rnethyl-1,2,3,4-tetrahydr'oisoquinoline.

A mixture of 26.1 g. of 1-(1-nitro-2'-naphthal)-2-methyl-1,2,3,4-tetrahydroisoquinoline, 4.0 g. of platinum oxide and 300ml. of absolute ethanol is hydrogenated for 25 minutes. After filtrationand concentration in vacuo, there is obtained, as the residue,1-(1'-amino-2-naphthylmethyl)-2-methyl-1,2,3,4-tetrahydroisoquinolinewhich on treatment with ethyl acetate-etheral hydrogen chloride,filtration and recrystallization frommethanol-ethanol gives 7 thedihydrochloride salt.

Example 2 A mixtureof 18.1 g. of 3,4-dimethoxyphenethylamine and 24.9 g.of l-nitro-2-naphthalene acetyl chloride in 300 m1. of benzene and 30ml. 10% sodium hydroxide is stirred'for two hours and filtered to give1-nitro-2-naph thyl-N- (3 ,4'-dimethoxyphenethyl) acetamide.

Ten grams of the above prepared acetamide is treated with 15 ml. ofphosphorus oxychloride in toluene. The mixture is refluxed for one hour,then cooled and treated with light petroleum to separate a. layer whichis decanted. The residue is treated with water and ammonia solution andextracted into chloroform. The chloroform extract is concentrated invacuo to give1-(1-nitro-2'-naphthylmethyl)-6,7-dirnethoXy-3,4-dihydroisoquinoline.

The resulting 3,4-dihydro-6,7-dimethoxy-1-(l-nitro-2-naphthylmethyl)isoquinoline is treated with methyl iodide in ethanolgives the methiodide salt.

. 3 V in benzene to give, after heating on a steam bath, cooling andevaporating the solvent,1-(l-nitro-2-naphthyhnethyl)-2-methyl-6,7-dimethoxy 3,4dihydroisoquinolinium iodide.

To a warm stirred solution of 10.0 g. of the above preparedisoquinolinium iodide derivative in methanol is added 5.0 g. of sodiumborohydride. The mixture is stirred for one hour, evaporated to drynessin vacuo and treated with chloroform and water. The chloroform layer iswashed with water and with saturated sodium chloride solution. and driedover sodium sulfate. The solvent is removed in vacuo. The residue istriturated with absolute ethanol to yield a solid which onrecrystallization from ethanol givesl-(l'-nitro-2'-naphthylmethyl)-2-methyl-6,7-dimethoxy 1,2,3,4tetrahydroisoquinoline. Reduction of the nitro group is accomplished bytreating with zinc dust and sulfuric acid at 15 C. The mixture isfiltered, made alkaline with ammonia and extracted with chloroform. Evaporating the extract to dryness and recrystallizing the residue fromethanol gives 1-( 1'-amino-2-naphthylmethyl) -2-methyl-6,7- dimethoxy-1,2,3,4-tetrahydroisoquinoline.

Example 3 By the procedure of Example 2,3,4-methylenedioxyphenethylamine is reacted with 1-nitro-2 naphthaleneacetyl chloride to givel-nitro-2-naphthyl-N-(3',4'-methylenedioxyphenethyl)acetamide which istreated with phosphorous oxychloride in toluene to yield 1(1'-nitro-2'-naphthylmethyl -6,7-methylenedioxy-3,4-dihydroisoquinoline.

Treating the above prepared dihydrosisoquinoline with methyl iodide andtreating the resulting methyl isoquinolinium iodide with sodiumborohydride in methanol followed by reduction of the nitro group usingzinc dust and sulfuric acid gives 1-(1'-amino-2-napl1thylmethyl)-2-methyl-6,7-methy1enedioxy-1,2,3,4-tetrahydroisoquinoline.

Treating the above prepared base with methyl iodide Similarly reactingthe base with ethyl p-toluenesulfonate in ethanol gives the ethylp-toluenesulfonate salt.

Ea'grzmple 4 According to the procedure of Example 1, S-methoxy-N-methylisoquinolinium iodide is reacted with 2-methy1-l-nitronaphthalene to give l-(1-nitro-2'-naphthal)-5-rnethoxy-Z-methyl-l,2,3,4-tetrahydroisoquinoline which is v hydrogenatedin ethanol using a platinum oxide catalyst to give1-(1-amino-2'-naphthylmethyl)-5-methoxy-2methyl-l,2,3,4-tetrahydroisoquinoline.

Similarly using 7-methoxy-N-methylisoquinolinium iodide as the startingmaterial1-(l-amino-2-naphthylmethyl)-7-methoxy-l,2,3,4-tetrahydroisoquinoline isobtained.

4 Example 6 A mixture of 13.5 g. of a-methylphenethylamine and 25.0 g.of 1-nitro-2naphthalene acetyl chloride in benzene and 10% sodiumhydroxide is stirred for two hours and filtered to give1-nitro-2-naphthyl-N-(u-methylphenethyl)- acetamide.

By the procedure of Example 2, the aboxe prepared acetamide is treatedwith phosphorus oxychloride in toluene to give1-(1-nitro-2'-naphthylmethyl)-3-methyl-3,4- dihydroisoquinoline whichistreated with methyl iodide in benzene to givel-(1'-nitro-2-naphthylmethyl)-2,3-dimethyl-3,4 dihydroisoquinoliniumiodide. This 3,4-dihydro compound is treated with sodium borohydride inmethanol followed by reduction with zinc dust and sulfuric acid to givel-(l-arnino-2-naphthylmethyl)-2,3-dimethyl-1,2,3,4-tetrahydroisoquinolinewhich on treatment with an excess of maleic acid in ethyl acetatee gavethe dimaleate salt.

This application is a continuation-in-part of Serial No. 229,992 filedOctober 11, 1962.

What is claimed is:

1. A compound of the class consisting .of a free base and its nontoxic,pharmaceutically acceptable, acid addition and quaternary ammoniumsalts, the free base having the formula:

XW/\ R1 I in which R is lower alkyl.

3. l-(1'-amino-2-naphthylmethyl)-2 methyl 1,2,3,4-tetrahydroisoquinoline.

No references cited.

1. A COMPOUND OF THE CLASS OF A FREE BASE AND ITS NONTOXIC,PHARMACEUTICALLY ACCEPTABLE, ACID ADDITION AND QUATERNARY AMMONIUMSALTS, THE FREE BASE HAVING THE FORMULA: